The PubMed database (http://www.pubmed.gov) was independently searched from January 1^st 2008 to March 31^st 2014 using the key words “abiraterone” and “metastatic castrate resistant prostate cancer” or “metastatic castration resistant prostate cancer”. In addition, we searched abstracts presented at the American Society of Clinical Oncology annual conferences from 2010 to 2014 using the same keywords. Selected abstracts and publications were reviewed for complete safety and efficacy information, and verified so that the most recent and up to date version was identified.

The goal of this study was to determine the impact of prior chemotherapy on the efficacy and toxicity of abiraterone in the treatment of metastatic CRPC. Therefore, we have included RCTs in which abiraterone plus prednisone was compared to placebo plus prednisone in patients with and without prior chemotherapy. All non-RCTs including phase 1 trials and single-arm phase 2 trials were excluded. Trials that met the following criteria were chosen for analysis: phase II or III prospective RCTs, patients with metastatic CRPC, and patients assigned to treatment with abiraterone plus prednisone or placebo plus prednisone. To assess study quality, the 7-item scale (score 0-5) Jadad Score was used for each included clinical trial[17].

Efficacy end points included overall survival (OS), defined from the date of randomization to the date of death from all causes, prostate-specific antigen (PSA) progression-free survival (PFS), and Radiographic-PFS. Radiographic-PFS was defined as progression on bone scanning defined by the Prostate Cancer Working Group 2 (PCWG2) criteria[18] or progressive soft-tissue lesions measured with the use of computed tomography or magnetic resonance imaging according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria[19]. PSA progression was defined by the PCWG2 criteria[18]. Additional clinical endpoints included PSA response rate (≥ 50% decline in PSA level from baseline) and rate of objective response based on the RECIST criteria[18,19].

Safety endpoints were based on the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Hypokalemia was categorized as grade 1: < 3.5 mmol/L, grade 3: < 3.0-2.5 mmol/L and, grade 4: < 2.5 mmol/L. Hypertension was categorized grade 1; asymptomatic, transient (< 24 h) increase by > 20 mmHg (diastolic) or to > 150/100 if previously within normal limit with no need for intervention, grade 2; recurrent or persistent (≥ 24 h) or symptomatic increase by > 20 mmHg (diastolic) or to > 150/100 if previously within normal limit; with monotherapy may be indicated, grade 3; requiring more than one drug or more intensive therapy than previously, and grade 4; life-threatening consequences such as hypertensive crisis. We also extracted safety data for various cardiac disorders: ischemic heart disease, myocardial infarction, supra-ventricular arrhythmia, ventricular tachyarrhythmias, cardiac failure, signs and symptoms. Edema and fluid retention was also included and was derived from edema-related adverse effects from sites such head and neck, trunk and genitals, limbs, and viscera.

All statistical analyses were performed using Comprehensive MetaAnalysis program version 2.0 (Biostat, Englewood, New Jersey, United States). Hazard ratios (HR), the median time of OS, time to PSA-PFS, time to Radiographic-PFS of patients in months, along with the proportion of patients showing PSA response rate and rate of objective response in both arms were extracted from the included clinical trials. Safety data-were collected included the number of patients with: all-grade and high-grade cardiac disorders, all-grade and high-grade hypertension, all-grade and high-grade fluid retention and edema, all-grade and high-grade hypokalemia respectively. Collected data were entered into a Microsoft Excel sheet. For each study, the proportion of patients, the relative risk (RR) was calculated and the 95%CI was derived. Because the two clinical trials were designed to have a control arm, the relative risk of safety outcome among patients assigned to abiraterone was calculated and compared to patients assigned to the control arm; in addition, the specific effect of abiraterone was calculated based on the incidence or response rate difference between abiraterone plus prednisone and placebo plus prednisone. For meta-analysis, both fixed-effects (weighted with inverse variance) and random-effects model were considered. Prior to the meta-analysis, Cochran’s Q statistic and I² were calculated to assess the heterogeneity among the proportions of the included trials. For a P value of < 0.1, the assumption of homogeneity was considered invalid. If invalid the random-effects model was used. If the assumption of homogeneity was valid both the fixed-effects and random-effects model results were reported. A two-tailed P value of < 0.05 was considered to be statistically significant.

Our literature search generated a total of 178 potentially relevant studies of abiraterone and metastatic CRPC. From these studies a total of 7 RCTs were identified, where 5 of them were excluded due to concomitant treatment with other agents [OGX-427, Sipuleucel-T, Trebanib (AMG-386), GDC-0068/GDC-0980]. Overall, two phase III RCTs were included in our final analysis[14,15] (Figure 1). Both trials included patients with metastatic CRPC; histologically or cytologically confirmed prostate cancer with disease progression based on PCWG2 criteria and ongoing androgen deprivation, with a serum testosterone level of ≤ 50 ng/dL[14,15]. In the COU-AA-301 trial, included patients had Eastern Cooperative Oncology Group (ECOG) performance status scores of ≤ 2 with established disease progression after receiving docetaxel (Table 1). COU-AA-302 included chemotherapy-naïve patients with disease progression, with good performance status (ECOG status ≤ 1) and Brief Pain Inventory-Short Form (BPI-SF) score of 0-3 (n = 1088). In an independent review, the Jadad Score was calculated for each included trial (Table 1). The COU-AA-301 study was given the highest Jadad score of 5, while COU-AA-302 was given a score of 4, based on the 7-item scale. In the COU-AA-302 trial, radiographic progression-free survival was measured by the study investigators, rather than by a blinded review[15].

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Figure 1 Selection of randomized controlled trials included in the meta-analysis. RCTs: Randomized controlled trials.

A total of 2283 patients diagnosed with metastatic CRPC from the two RCTs were available for the analysis. A total of 1343 (58.3%) patients received the approved United States Food and Drug Administration abiraterone oral dose of 1 g daily with 5 mg of prednisone twice daily by mouth. Finally, 546 patients in the pre-chemotherapy and 797 in the post-chemotherapy arms were included in the meta-analysis (Table 2). In the post-chemotherapy trial, 70% in the abiraterone arm and 69% in the control arm received one previous cytotoxic chemotherapy regimen and approximately 30% in the abiraterone arm and 31% in the control arm received two distinct previous regimens[14]. All included patients received at least one previous cytotoxic chemotherapy regimen containing docetaxel: docetaxel after a treatment break, single therapy with docetaxel, or docetaxel in combination with other agents[14].

Based on the meta-analysis of the two trials (Figure 2), the summary hazard ratio of OS associated with abiraterone acetate in comparison with the placebo yielded an increase in the OS (HR = 0.74, 95%CI: 0.66-0.84, P≤ 0.001). An increase in OS was also seen in the pre-chemotherapy study (HR = 0.75, 95%CI: 0.61-0.93, P < 0.01) and post-chemotherapy study (HR = 0.65, 95%CI: 0.54-0.78, P < 0.001) respectively. However there was no significant difference in HR between the two settings (Heterogeneity test: Q = 0.01, I² < 0.001, P = 0.92).

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Figure 2 Overall survival of abiraterone with prednisone vs placebo with prednisone. Hazard ratio (HR) associated with abiraterone with prednisone vs placebo with prednisone for overall survival, was calculated using fixed effects model. The HR and 95%CI for each trial and the final combined results are demonstrated numerically on the left and graphically as a forest plot on the right. For individual trials: filled in square, HR; lines, 95%CI; diamond plot, overall results of the included trials. OS: Overall survival.

Overall, abiraterone in comparison to placebo significantly reduced the risk of PSA-PFS (HR = 0.52, 95%CI: 0.45-0.59, P < 0.001), which was also seen in the pre-chemotherapy (HR = 0.49, 95%CI: 0.42-0.57, P < 0.001) and post-chemotherapy settings (HR = 0.63, 95%CI: 0.47-0.84, P = 0.002). Even though HR with pre-chemotherapy was lower than post-chemotherapy (Figure 3), there was no significant difference in the risk reduction of PSA-PFS associated with abiraterone between the two settings (Heterogeneity test: Q = 2.255, I² = 55.648, P = 0.13).

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Figure 3 Prostate specific antigen progression-free survival of abiraterone with prednisone vs placebo with prednisone. Hazard ratio (HR) associated with abiraterone with prednisone vs placebo with prednisone for PSA-PFS were calculated using fixed effects model. The HR and 95%CI for each trial and the final combined results are demonstrated numerically on the left and graphically as a forest plot on the right. For individual trials: filled in square, hazard ratio; lines, 95%CI; diamond plot, overall results of the included trials. PSA: Prostate specific antigen; PFS: Progression-free survival.

As shown in Figure 4, radiographic-PFS was significantly increased with abiraterone in comparison with placebo (summary HR = 0.60, 95%CI: 0.48-0.75, P < 0.001) in the pre-chemotherapy setting (HR = 0.53, 95%CI: 0.45-0.62, P < 0.001) and the post-chemotherapy setting (HR = 0.67, 95%CI: 0.58-0.78, P < 0.001). There was significant difference between the pre- and post-chemotherapy settings (Heterogeneity test: Q = 4.207, I² = 76.203, P = 0.035).

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Figure 4 Radiographic progression-free survival of abiraterone with prednisone vs placebo with prednisone. Hazard ratio (HR) associated with abiraterone with prednisone vs placebo with prednisone for Radiographic-PFS were calculated using random effect model. The HR and 95%CI for each trial and the final combined results are demonstrated numerically on the left and graphically as a forest plot on the right. For individual trials: filled in square, hazard ratio; lines, 95%CI; diamond plot, overall results of the included trials. PFS: Progression-free survival.

Overall, abiraterone compared to placebo significantly increased PSA response rate (summary RR = 3.62, 95%CI: 1.78-7.40, P < 0.001) in the pre-chemotherapy setting (RR = 2.58, 95%CI: 2.19-3.04, P < 0.001) and the post-chemotherapy setting (RR = 5.36, 95%CI: 3.52-8.17, P < 0.001). There was significant difference between the pre-chemotherapy setting and the post-chemotherapy setting (Heterogeneity test: Q = 4.207, I² = 76.203, P = 0.04).

In addition, we determined the specific effect of abiraterone on PSA response (PSA response rate of abiraterone and prednisone minus placebo and prednisone in the same trial). As shown in Table 2, pre-chemotherapy (38.0%, 95%CI: 34.0%-42.1%) had significantly higher PSA response rate attributable to abiraterone (P < 0.001) than post-chemotherapy (24.0%, 95%CI: 21.2%-27.1%).

The rate of object response with abiraterone in comparison to placebo, was significantly increased (summary RR = 3.02, 95%CI: 1.55-5.90, P < 0.001). The difference between the post-chemotherapy setting (RR = 4.49, 95%CI: 2.57-7.830, P < 0.001) and the pre-chemotherapy setting (RR = 2.25, 95%CI: 1.80-2.81, P < 0.001) significantly favored the pre-chemotherapy setting (Heterogeneity test: Q = 4.207, I² = 76.203, P = 0.04). In addition, we determined the specific effect of abiraterone on objective response (objective response rate of abiraterone and prednisone minus placebo and prednisone). As shown in Table 2, there was significant difference (P < 0.001) in objective response rate attributable to abiraterone between pre-chemotherapy (20.0%, 95%CI: 16.9%-23.6%) and post-chemotherapy (11.5%, 95%CI: 9.5%-13.9%).

Overall, abiraterone significantly increased the risk of all-grade cardiac disorders (RR = 1.25, 95%CI: 1.02-1.52, P = 0.03), fluid retention and edema (RR = 1.27, 95%CI: 1.08-1.49, P =0.004), hypertension (RR = 1.58, 95%CI: 1.27-1.98), and hypokalemia (RR = 1.60, 95%CI: 1.06-2.42, P = 0.027). In addition, abiraterone significantly increased the risk of high-grade cardiac disorders (RR = 2.17, 95%CI: 1.37-3.45), but not high-grade fluid retention and edema, hypertension, and hypokalemia (Table 3) based on the summary results of the two trials. Subgroup analyses showed there was significant difference between pre- and post-chemotherapy in the risk of high-grade fluid retention and edema (P = 0.02) and hypokalemia (P = 0.02) associated with abiraterone.

We further determined the incidence rate attributable to abiraterone (incidence rate of abiraterone and prednisone minus placebo and prednisone). The summary incidence of all-grade fluid retention and edema attributable to abiraterone was 6.1% (95%CI: 2.7%-13.2%). Post-chemotherapy was associated with significantly higher risk of all-grade fluid retention/edema attributable to abiraterone than pre-chemotherapy (9.0% vs 4.0%, P < 0.001). Similarly, post-chemotherapy was associated with significantly higher risk of all-grade hypokalemia attributable to abiraterone than pre-chemotherapy (9.0% vs 4.0%, P < 0.001). In contrast, pre-chemotherapy was associated with significantly higher risk of all-grade hypertension attributable to abiraterone than post-chemotherapy (3.0% vs 9.0%, P < 0.001).

Chemotherapy with docetaxel plays an important role in the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone, an androgen biosynthesis inhibitor, has been shown to improve overall survival in metastatic CRPC patients who have not received previous chemotherapy. It is not clear that prior chemotherapy affects the effectiveness of abiraterone. The authors performed a meta-analysis to compare the efficacy and safety of abiraterone in patients with and without prior chemotherapy.

In the setting of metastatic CRPC, the optimal sequence of abiraterone in relation to chemotherapy to achieve the greatest survival benefit is a topic of emerging interest. In a previous meta-analysis of abiraterone for treatment of metastatic CRPC, abiraterone compared to placebo significantly prolonged OS and radiographic-PFS. These results support the efficacy of abiraterone in metastatic CRPC.

This meta-analysis has demonstrated that pre-chemotherapy may affect the efficacy and toxicity of abiraterone treatment in patients with metastatic CRPC. Abiraterone was associated with significantly increased radiographic-PFS, objective response rate, and prostate-specific antigen (PSA) response rate in the pre-chemotherapy setting when compared to the post-chemotherapy setting.

Abiraterone should be considered as a first-line choice in patients who cannot tolerate chemotherapy or have asymptomatic disease. However studies with larger sample size and are required to compare abiraterone in pre and post chemotherapy setting and to compare the efficacy with other new androgen signaling blocking agents.

Radiographic-PFS was defined as progression on bone scanning based on the Prostate Cancer Working Group 2 (PCWG2) criteria or progressive soft-tissue lesions measured with the use of computed tomography or magnetic resonance imaging according to the modified Response Evaluation Criteria in Solid Tumors. PSA progression is defined as a a 25% or greater increase and an absolute increase of 2 ng/mL or more from the nadir is documented and confirmed by a second value obtained 3 or more weeks later, also based on the PCWG2 criteria.

The study was clinically relevant and addressed the important topic of abiraterone sequencing in metastatic castrate resistant prostate cancer. The article provides a succinct yet relevant discussion about the impact of prior chemotherapy in the treatment of this clinical entity.